Jeff Settleman

Senior Director and Staff Scientist, Discovery Oncology

Postdoc Mentor

Staff Scientist

"I find this to be an extremely exciting time in the history of oncology research."

5
years at Genentech

21
publications (2009-14)

12
awards & honors

I joined Genentech in 2010, after having spent the previous 18 years on the faculty of Harvard Medical School. The move to Genentech was largely prompted by my steadily growing interest in the pursuit of novel therapeutic opportunities in cancer based on the rapidly accumulating understanding of molecular mechanisms underlying oncogenic processes and the response to drug treatment. I have found the research environment at Genentech to be remarkable in many respects. There is a very high bar for quality research, and decisions are always driven by the science. It’s been inspiring and exciting to work closely with such talented colleagues on such an important problem.

Postdoctoral Mentor

Being a post-doc mentor is very rewarding at several levels. It gives me the opportunity to “re-experience” the excitement of discovery that I enjoyed tremendously as a “bench scientist” many years ago when I was still performing experiments with my own hands. It’s also very satisfying to watch the development of young scientists as they mature in their approach to experimental design and data interpretation. My most important roles as a post-doc mentor are to maintain a stimulating lab environment, and to remind post-docs to pursue the most important questions and to continuously ask themselves whether they are taking the best approach to answering those questions.

Several recent “rationally-targeted” anti-cancer drugs have defined a paradigm shift in cancer therapy. However, progression during therapy is inevitable due to the acquisition of drug resistance. For many drugs, specific genetic mechanisms of resistance have been elucidated, and pre-clinical findings implicate additional non-genetic mechanisms. Moreover, accumulating evidence implicates heterogeneity within cancer cell populations in the response to drug treatment, posing an additional challenge to the development of cancer therapeutics.

While modeling the acute response to various anti-cancer agents in drug-sensitive tumor cell lines, we consistently observe a small subpopulation of reversibly “drug-tolerant” cells. This drug-tolerant phenotype, associated with a distinct chromatin state, is transiently acquired and relinquished at low frequency by individual cells within the population, implicating the dynamic regulation of phenotypic heterogeneity in drug tolerance. These findings suggest that cancer cell populations may employ an epigenetically-regulated dynamic survival strategy in which individual cells transiently assume a reversibly drug-tolerant state to protect the population from eradication by potentially lethal exposures.

Cancer cells typically express multiple receptor tyrosine kinases (RTKs) that mediate signals that converge on common critical downstream cell survival effectors - most notably, phosphatidylinositol 3-kinase and mitogen-activated protein kinase. Consequently, increased RTK ligand levels, via autocrine tumor cell production, paracrine contribution by tumor stroma, or systemic production, could confer resistance to inhibitors of an oncogenic kinase with a similar signaling output. Using a panel of kinase-“addicted” cancer cell lines, we found that most cells can be “rescued” from drug sensitivity by simply exposing them to one or more RTK ligands. These observations highlight the extensive redundancy of RTK-transduced signalling in cancer cells and the potentially broad role of widely expressed RTK ligands in innate and acquired resistance to drugs targeting oncogenic kinases.